by chiral thiolate-bridged diruthenium complexes to give the
corresponding propargylated products in good yields with a
high enantioselectivity (up to 94% ee).5 This was the first
example of asymmetric Friedel-Crafts propargylation of
aromatic compounds. As an extension of our study, we have
now found the ruthenium-catalyzed enantioselective prop-
argylation of indole derivatives with propargylic alcohols.6
A remarkable effect of the nature of N-substituent of indoles
was observed on the enantioselectivity of the produced
propargylated indoles, although the N-substituent is relatively
apart from the reactive â-position of indoles. Thus, the
introduction of a bulky group such as tert-butyldimethylsilyl
or triisopropylsilyl group at the nitrogen atom of indole
dramatically increased the enantioselectivity of the propar-
gylated indoles. A preliminary result of enantioselective
propargylation of indoles is described here.
Treatment of 1-phenyl-2-propyn-1-ol (1a) with indole (10
equiv to 1a) in ClCH2CH2Cl in the presence of a catalytic
amount of a chiral thiolate-bridged diruthenium complex,
which was prepared in situ from the tetranuclear ruthenium-
(II) complex [Cp*RuCl]4 and a chiral disulfide (2a)7 in THF
(tetrahydrofuran) at room temperature for 12 h, and NH4-
BF4 at 60 °C for 3 h afforded 3-(1-phenyl-2-propynyl)indole
(3a) in 71% isolated yield with 35% ee (Scheme 1; Table 1,
Table 1. Ruthenium-Catalyzed Enantioselective Propargylation
of Indoles with Propargylic Alcohol (1a)a
R of indole
(equiv to 1a)
run
T (°C) time (h) yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
H (10)
Me (10)
PhCH2 (10)
Ph (10)
60
60
60
60
60
60
60
40
40
3
3
3
3
3
3
3
7
7
3a, 71
3b, 77
3c, 68
3d, 74
3a, -
3e, 63
3f, 74
3f, 70
3f, 77
35
61
41
40
37d
73
75
82
78
SiMe3 (10)
t
SiMe2 Bu (10)
SiiPr3 (10)
SiiPr3 (10)
SiiPr3 (3)
a All reactions of 1a (0.20 mmol) with indole were carried out in the
presence of a ruthenium complex (0.010 mmol, generated in situ from
[Cp*RuCl]4 and 2a) and NH4BF4 (0.020 mmol) in ClCH2CH2Cl (5 mL).
b Isolated yield of 3. c Determined by HPLC (see the Supporting Information
for experimental details). d The ee value of 3a.
butoxycarbonyl (Boc) group was used as N-substituent of
indole. The use of N-(trimethylsilyl)indole resulted in the
formation of only 3a with 37% ee (Table 1, run 5), indicating
that the deprotection of the trimethylsilyl group easily
proceeded before the propargylation of N-(trimethylsilyl)-
indole. The introduction of a bulky silyl group such as a
tert-butyldimethylsilyl or triisopropylsilyl moiety gave the
corresponding propargylated indoles with much higher
enantioselectivity (Table 1, runs 6 and 7). The reaction of
N-(triisopropylsilyl)indole proceeded similarly even at 40 °C
(Table 1, run 8). Even the use of 3 equiv of N-(triisopro-
pylsilyl)indole to 1a worked well (Table 1, run 9). As
reported in our previous paper,5 a similar enantioselectivity
of propargylation of aromatic compounds such as 2-meth-
ylfuran and N,N-dimethylaniline with 1a has been observed
using 2a as a chiral ligand.
Scheme 1
The catalytic propargylation of N-(triisopropylsilyl)indole
(3 equiv to 1) with other propargylic alcohols (1) was
investigated at 40 °C by using 2a as a chiral ligand. Typical
results are shown in Table 2. The presence of a substituent
in the benzene ring of the propargylic alcohols had some
effect on the enantioselectivity. The introduction of a methyl
group at the para position of the benzene ring of 1a slightly
decreased the enantioselectivity (Table 2, run 2), while the
introduction of a phenyl group at the para or ortho position
of the benzene ring of 1a increased the enantioselectivity
(Table 2, runs 4 and 5). When 1-(1-naphthyl)-2-propyn-1-
ol (1g) was used as a substrate, the highest enantioselectivity
was achieved (Table 2, run 7).
The propargylation of other N-(triisopropylsilyl)indoles
bearing a substituent at 5-position of the indole ring with 1g
under similar reaction conditions afforded a good yield of
products with a high enantioselectivity, irrespective of the
nature of the substituent (Table 3). On the other hand, the
introduction of a substituent at 2-position of the indole ring
dramatically decreased the enantioselectivity of the product.
To obtain more information about the enantioselective
propargylation of aromatic compounds, the stereochemistry
of the propargylated product 3l was determined. The reaction
run 1). The introduction of a methyl group as N-substituent
of indole much improved the enantioselectivity (Table 1, run
2), in contrast to the presence of a bulky group such as a
benzyl or phenyl moiety as the N-substituent of indole (Table
1, runs 3 and 4). No reaction occurred at all when a tert-
(5) Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int.
Ed. 2007, 46, 6488.
(6) Recently, propargylation of indoles catalyzed by iodine,6a Sc(OTf)3,6b
InCl3,6c Amberlyst-15,6d and FeCl36e has been reported, but enantioselective
propargylation has not yet been reported until now. (a) Liu, Z.; Liu, Z.;
Shafiq, Z.; Wu, Y.-C.; Wang, D.; Chen, Y.-J. Tetrahedron Lett. 2007, 48,
3963. (b) Yadav, J. S.; Reddy, B. V. S.; Rao, K. V. R.; Kumar, G. G. K.
S. N. Tetrahedron Lett. 2007, 48, 5573. (c) Liu, Z.; Liu, L.; Shafiq, Z.;
Wu, Y.-C.; Wang, D.; Chen, Y.-J. Synthesis 2007, 1961. (d) Yadav, J. S.;
Reddy, B. V. S.; Kumar, G. G. K. S. N.; Rao, K. V. R. Chem. Lett. 2007,
36, 942. (e) Jana, U.; Maiti, S.; Biswas, S. Tetrahedron Lett. 2007, 48,
7160.
(7) Inada, Y.; Nishibayashi, Y.; Uemura, S. Angew. Chem., Int. Ed. 2005,
44, 7715.
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Org. Lett., Vol. 9, No. 26, 2007